It has been estimated that the USA invests more than $178 billion dollars annually in direct and indirect costs to control Alzheimer Disease (AD). With a percentage of the population over 65 years old (in Chile it is over 12%), the number of people with AD will increase rapidly and proportionally. If early diagnosis technologies for AD are not found soon, as well as interventions for its treatment, the number of people who will develop the disease will surpass health systems. Since our group has conducted research for more than 30 years in this field and we have made some of the most relevant discoveries in the world, we are in the best position to innovate and find effective solutions for its prevention, early detection and treatment. Thus our findings contribute to AD prevention, to its diagnosis (molecular markers and neuroimage technologies), and now to its treatment. We are developing new drugs for controlling the disease, in addition to cognitive stimulation technologies through software designed to improve patients' quality of life and to correct memory disorders. We now offer a pharmaceutical formulation that, according to our previous research, helps to prevent and control brain disorders leading to AD and other neurodegenerative diseases, among them oxidative stress, neuroinflammation and the gradual loss of neurons.
At present the FDA has approved only 5 drugs for AD treatment, and the use of some of them has been extended to other dementias (vascular dementia, Lewy bodies dementia, frontotemporal dementia due to taupathies, etc.) (Maccioni & Perry, 2009).
Four of them inhibit AChE enzyme (acetil colinesterasa) and their pharmacologic activity is aimed at compensating the cholinergic loss taking place in AD. None of them succeeds in healing this pathology and their action is rather palliative, diminishing the progress of symptoms, as they do not control AD's etiopathogenesis. These drugs are: Tacrine® (almost not used any more due to its hepatotoxic condition), Donepecil, Rivastigmine and Galantamine. The last three cover more than 80% of the markets and in spite of their very low effectiveness their sales amount to billions of dollars around the world.
Each one of them is sold in pharmaceutic forms under commercial names given by different laboratories which produce and put them on the market. They are highly expensive but have not managed to stop the disease's progression. The other drug is Memantine, which acts at another level, on NMDA receptors blocking exitotoxicity processes and the entrance of calcium into brain cells. Its market is still reduced as it has been commercialized for a shorter period of time. Its use is reserved essentially for advanced stages of the disease, but it is also palliative as it does not heal AD due to its incapacity to control endogenous mechanisms leading to the pathogenesis of this disease. On the other hand, other molecules are undergoing research and clinical testing, for example: (i) growth factors such as Cerebrolysin® which could be promising if the action—not yet demonstrated—of neurotrophic factors can be proven, and (ii) inhibitors of gamma secretase and vaccines guided towards senile plaques, definitively not effective due to the fact that senile plaques, neuropathological alterations formed by beta amiloid, are not responsible for AD and recent studies strongly disprove the amiloid hypothesis. These drugs, in which several pharmaceutic industries have invested billions of dollars, have not been successful because they do not respond to modern hypothesis of the pathology, as the tau and neuroimmunomodulation hypotheses (Maccioni & Perry, 2009).
AD's pathogenesis is directly related to the self aggregation of tau as the common final path for altered mechanisms of signal transduction between glial and neuronal cells, as a result of a series of danger signals in which innate immunity phenomena are involved (Maccioni et al., 2009). Therefore two types of the latest generation drugs would be the most promising for an effective AD treatment and could in the future replace the five first-generation molecules that have not proven to be effective. These new molecules are:
a) Inhibitors of the tau pathologic autoagregation in PHF-type filaments and finally in neurofibrillary tangles (NFTs), among which the drugs of our patent are present, the “quinolines”, and exert an effective action at this level.
b) Modern antiinflammatories that control over activation of TNF α proinflammatory cytokine, including etanercept.
The significant progress in the knowledge of the molecular aspects promoting neurodegeneration in relation to cognitive deterioration, including the changes in the functioning of the tau protein, inflammatory processes and oxidative stress, among others (Maccioni et al., 2001, 2006, 2009, Quintanilla et al., 2004; Orellana et al., 2005; Fernández et al., 2008; Farias 2010), is contributing nowadays to a more open-minded attitude in the search of new tools to treat these disorders. In Chile the prevalence of cognitive deterioration in the population, based for this diagnosis on a MiniMental<13 score is 7.9% in the age between 60-69 years, 18% between 70-79 years and 48% at 80 or more. It is estimated that the population with this kind of deterioration is over 280,000 people (Ministry of Health). This same study revealed a significant greater prevalence according to the literacy level: for people with only primary studies, the prevalence was 20.3%, for those with high school studies, 3.7% and for those with university studies, 2.6% (Ministry of Health, First Health Survey, 2003).
Neurodegenerative disorders are linked to an extensive and gradual neuronal loss, and associated to the ethiopathogenesis of this illness are the tau neurotoxic aggregates as well as the neurofibrillary tangles (NFTs). These are formed by a protein associated to the neuronal cytoskeleton named tau, which is hyperphosphorylated in the brains of AD patients (Kurt et al., 1997; Maccioni et al., 2001; Maccioni et al., 2004). Via unknown mechanisms, tau undergoes important modifications such as abnormal phosphorylation due to the deregulated activity of various kinases and phosphatases affecting their normal biological function (Zambrano et al., 2004). Under these circumstances tau begins to aggregate itself and produces NTFs, which are structures constituting a hystopathological marker, characteristic of AD (Maccioni et al., 2003).
The product of our neuroprotective formulation blocks the neuroinflammatory processes where the hyperphosphorylation of the tau protein takes place (Maccioni et al., 2009). On the basis of our hypothesis of the presence of tau in the ethiopathogenesis of AD, we have been researching on the disaggregating action of different molecules on NFTs, the main hystopathological injury found in brains of individuals presenting this pathology. After several attempts with drugs that disassemble amyloid's senile plaques, most of the efforts made worldwide to control cognitive disorders are being directed at present towards molecules with antiinflammatory activity and neuroprotectors.
In this context, and due to the dramatic increase in life expectancy at the global level, to find viable solutions for the treatment of cognitive disorders constitutes one of the greatest challenges faced by the pharmaceutical and biotechnological industry. There exist very few effective pharmaceutical formulations that act as neuroprotectors or cognitive function restorers; among them the most recent is Memory XLR, which contains essentially vitamins and S-adenosylmetionin and has shown relatively promising results at the clinical level (Chan and Shea, 2007). This confirms the enormous importance of generating natural products with nutraceutical activity that stimulate brain function, with no adverse effects for human beings, and with a tested efficiency and safety. This is the foundation of our effort to generate a formulation containing a nutraceutic with a highly antioxidant potential. Our nutraceutical formulae contains more than 96 times the antioxidant power present in cranberry concentrates and Noni, among others, measured by the TAR index, the Total Antioxidant Reactivity and evaluated in TROLOX equivalents. Thus our nutraceutic combines its high potency antioxidant effects with vitamins B6 and B12 plus folic acid, all of them key neuroprotective elements for brain activity and also for avoiding cognitive deterioration. The nutraceutic belonging to this formulation is a 100% native product, the “Andean Shilajit”, obtained from millenarian organic concentrates derived from bryophyt plants from the north of Chile, found in the subsoil of arid zones, with a high acid fulvic content, a product with a proven antioxidant power in addition to an anti-inflammatory activity. Besides these characteristics favoring brain health, folic acid jointly with vitamin B12 are key components to halt metabolic processes generating homocysteine, a neurotoxic activity. High homocysteine anaemia in patients is an important risk factor for cognitive deterioration. Moreover, vitamin B12 has a synthesis which decreases in the brain as people begin to age so it is advisable to supplement it.